Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase β, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL.

Original publication

DOI

10.1016/j.mrfmmm.2014.02.005

Type

Journal article

Journal

Mutat Res

Publication Date

04/2014

Volume

762

Pages

32 - 39

Keywords

2-Deoxyribonolactone, 8-Oxo-7,8-dihydro-2′-deoxyguanosine, Base excision repair, Clustered DNA damage, Mutation, Oxidized abasic sites, Biological Assay, DNA Breaks, Double-Stranded, DNA Polymerase beta, DNA Repair, Deoxyguanosine, Escherichia coli, Escherichia coli Proteins, Flap Endonucleases, Furans, Gamma Rays, Gene Expression Regulation, Bacterial, Mutagenesis, Mutation, Plasmids, Sugar Acids